FR2998298A1 - SYNTHESIS OF IMIDAZO [1,2-A] PYRAZIN-4-IUM SALTS FOR THE SYNTHESIS OF 1,4,7-TRIAZACYCLONONANE (TACN) AND ITS N- AND / OR C-FUNCTIONALIZED DERIVATIVES - Google Patents

Abstract

The present invention relates to a compound of formula (V ') The invention also relates to the process for synthesizing compound (V') and its use for the preparation of 1,4,7-triazacyclononane (tacn) and its derivatives Net or C-functionalized, in particular compounds of formula (I) The invention also relates to metal complexes comprising a ligand of formula (I) and a metal and their use for imaging.

Description

SYNTHESIS OF IMIDAZO [1,2-a] PYRAZIN-4-IUM SALTS FOR THE SYNTHESIS OF 1,4,7-TRIAZACYCLONONANE (TACN) AND ITS N- AND / OR C-FUNCTIONALIZED DERIVATIVES FIELD OF THE INVENTION The present invention relates to a new method of synthesis of the 1,4,7-triazacyclononane precursor (tacn) and its N- and / or C-functionalized derivatives. The process of the invention comprises the preparation of imidazo [1,2-a] pyrazin-4-ium salts useful for the synthesis of tacn and its N- and / or C-functionalized derivatives. The invention also relates to novel N- and / or C-functionalized macrocyclic molecules derived from tacn as well as to imidazo [1,2-a] pyrazin-4-ium salts. STATE OF THE ART Polyazamacrocycles and their derivatives are nitrogenous macrocycles known for their sequestering properties vis-à-vis transition metals and heavy metals. They find applications in fields as varied as liquid purification, catalysis, or even health, and more particularly medical imaging. Among these macrocyclic systems, derivatives of tridentate ligand 1,4,7 triazacyclononane (tacn), macrocycle carrier of three nitrogen atoms, have very good complexing properties, making them likely to be used in many applications. In particular, the ability of tacn nitrogen derivatives to stabilize metal ions of high oxidation state, and in particular Manganese (Mn (IV)), explains its involvement in many catalytic processes, such as in polymerization reactions. olefins or epoxidation reactions of olefins with hydrogen peroxide in water (Sibbons et al., Dalton Trans., 2006, 645-661). In this context, the trimethyl-tacn (metacn) system has been particularly studied for its catalytic activity in the form of dinuclear manganese complexes. Tacn-Mn (IV) complexes have also been proposed as bleaching agents, especially in detergents, to replace certain oxidizing agents (W001 / 64826). The tacn derivatives have also been described as cosmetic agents for perms, or as keratin extraction agents (FR 2 862 217, WO2005 / 049870). The craze for tacn derivatives has been growing steadily for the past ten years, mainly due to the advantages that this type of system can offer for the sequestration of radiometals for nuclear imaging applications TEMP (MonoPhotonic Emission Tomography) and PET (Positron Emission Tomography). These macrocyclic molecules are then used as a bifunctional chelating agent, capable on the one hand of sequestering the radioactive source (In, Ga, Cu, Y, ...) and on the other hand of ensuring the coupling with a biomolecule vector. This method of indirect labeling is today a method of choice for medical imaging or for radioimmunotherapy.

Among the tacn derivatives frequently used in imaging is the NOTE, which corresponds to the tacn bearing three functions methylcarboxylate at the level of the nitrogen atoms. Various physicochemical and structural studies have been carried out on the NOTA complexes intended for TEMP / PET imaging or for therapy and have notably shown that the 64Cu-NOTA and 67 / 68Ga-NOTA metal complexes exhibit good stability in vivo. The radiolabeling kinetics is also relatively fast, requiring mild radiometallation conditions, compatible with labeling of antibody-like biological molecules (see for example US2012 / 064003, WO2009 / 079024, US2011 / 0070157). In order to improve current systems, efforts have focused on optimizing their properties, in particular by developing C-functionalized macrocycles. C-functionalization is an approach that consists in introducing a function called "grafting" on the carbon skeleton of the macrocycle. The C-functionalization of tacn can optionally be accompanied by the addition of chelating arms at the three nitrogen atoms of the cycle. This approach has been applied for the synthesis of new bifunctional chelating agents. It remains however relatively limited because of the difficulties of synthesis of the C-functionalized macrocycles. Access to such so-called "chelating bifunctional" systems requires, on the one hand, a method of efficient synthesis of the "basic" macrocycle, here the tacn motif, and on the other hand of being able to selectively functionalize the latter at the atomic level. nitrogen (N-functionalization) and / or at the level of the carbon skeleton (C-functionalization). To the knowledge of the Applicant, a single synthetic route is used to date for the synthesis of 1,4,7-triazacyclononane (tacn) and its N-functionalized analogues, known as "Richman cyclization. Atkins' (Richmans, JE, Atkins, TJJ Am Chem Soc 1974, 96, 2268-2270). The tacn synthesis pathway described by Richman and Atkins is summarized in Scheme 1 below: Ts DMF Ts-N, N H2SO4 -N-Na + + TsO / Ts Ts-N D N-Na + TsO 1-2 h 100 ° C. 48 h 1 Ts Scheme 1. Richman-Atkins Cyclization This synthesis method has several disadvantages, including the use of tosyle groups during the cyclization step, high reaction times and an overall yield not exceeding 12%. The drastic conditions of elimination of tosyle groups (H2504, 100 ° C for 2 days) are a major obstacle to transpose this process on a large scale, besides this synthetic route is very uneconomical in terms of the number of atoms put The "Richman-Atkins" cyclization conditions have been used for the preparation of C-functionalised derivatives starting from diols or linear amines functionalized on one of the carbon atoms (Argouarch et al., Tetrahedron Lett. 2002, 43, 3795-3798, Argouarch et al., Org Biomol Chem, 2003, 1, 2357-2363, Stones et al., Org Biomol Chem, 2003, 1, 4408-4417, Scheuermann et al. Biomol, Chem., 2004, 2, 2664-2670, Mc Murry et al., Bioconjugate, 1993, 4, 236-245). As the introduction of the function at the level of the carbon skeleton can not be achieved by simple C-C coupling, these syntheses use biselectrophile synthons bearing the desired functionality. Being directly inspired by the method of obtaining tacn according to Richman and Atkins, this method of synthesis implies drastic deprotection conditions considerably limiting the nature of the functional groups that can be introduced on the macrocycle. A synthetic process giving access to C-functionalized derivatives has recently been described by J.M. Kohlen's team (Koek J. and Kohlen E., Tetrahedron Lett., 2006, 47, 3673-3675). In this process, the methyl functionalized tac on the nitrogen atoms (metacn) is oxidized by N-bromosuccinimide (NBS) to yield the corresponding bicyclic iminium. The addition of potassium cyanide opens the bicyclic structure and forms a 9-membered ring. The reduction of the nitrile group makes it possible to form an amine function that allows subsequent functionalization. ## STR1 ## N ---- Me Diagram 2. C-Functionalization of Kohlen et al. This synthetic route however requires prior synthesis of the metacn by cyclization of Richman-Atkins. Moreover, it remains very limited since it allows access only C-functionalized derivatives of metacn. Indeed, the methyl groups can not be removed and this approach does not allow in particular the preparation of tacn derivatives bearing coordinating groups on the nitrogen atoms (carboxylates, phosphonates ...) useful for medical imaging applications. Thus, despite the high potential of C-functionalized tacn systems, very few molecules of this type are described today, mainly because of the difficulties of synthesis. The present invention therefore proposes a new method for synthesizing the 1,4,7-triazacyclononane precursor (tacn) and its N- and / or C-functionalized derivatives. The process of the invention comprises the synthesis of imidazo [1,2-a] pyrazin-4-ium salts. The invention also relates to novel macrocyclic molecules derived from tacn as well as salts of imidazo [1,2-a] pyrazin-4-ium. DEFINITIONS In the present invention, the terms below are defined as follows: "aliphatic group" refers to any carbon, acyclic or cyclic group, saturated or unsaturated, branched or unbranched, optionally substituted, with the exception of aromatic compounds . According to the invention, an aliphatic group preferably comprises from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms. According to a preferred embodiment of the invention, the branched or unbranched aliphatic groups are chosen from alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups; "Alkyl" relates to any saturated linear or branched hydrocarbon chain, optionally substituted, having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms; more preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; "Cycloalkyl" relates to a cyclic or polycyclic alkyl group, optionally branched, substituted or unsubstituted; preferably a cyclopropyl, cyclopentyl or cyclohexyl group; "Alkenyl" relates to any hydrocarbon chain, linear or branched, optionally substituted, bearing at least one double bond and having from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms; "Cycloalkenyl" refers to a cyclic or polycyclic alkenyl group, optionally branched, substituted or unsubstituted; preferably a cyclopropyl, cyclopentyl or cyclohexyl group; "Alkynyl" relates to any hydrocarbon chain, linear or branched, optionally substituted, bearing at least one triple bond and having from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms; "Alkoxy" refers to an O-alkyl group. A preferred alkoxy group in the present invention is methoxy; "Aromatic group" relates to a mono- or polycyclic system of 5 to 20, preferably 6 to 12, carbon atoms having one or more aromatic rings (when there are two rings, it is referred to as a biaryl) among which mention may be made of the phenyl group, the biphenyl group, the 1-naphthyl group, the 2-naphthyl group, the tetrahydronaphthyl group, the indanyl group, and the binaphthyl group. The term "aromatic group" also refers to any aromatic ring comprising at least one heteroatom chosen from an oxygen, nitrogen or sulfur atom. The aromatic group may be substituted with 1 to 3 substituents chosen independently of one another, from a hydroxyl group, a linear or branched alkyl group comprising 1, 2, 3, 4, 5 or 6 carbon atoms, in particular methyl, ethyl, propyl, butyl, an alkoxy group or a halogen atom, especially bromine, chlorine and iodine. When the aromatic group is substituted, it may be meso and / or para and / or ortho substituted; - "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are bromo and iodo. - "heteroatom" refers to nitrogen, oxygen, sulfur or phosphorus atoms; "Amino" refers to an -NH 2 group or to any group derived from -NH 2 by substitution of one or more hydrogen atoms for a substituted or unsubstituted aliphatic or aromatic organic group. Preferably, the groups derived from -NH 2 are alkylamino groups, that is to say N-alkyl groups, comprising the monoalkylamino and dialkylamino groups. "Function likely to lead to chemistry click reactions" concerns chemical functions such as azide, alkyne, norbornene, cyclooctene, or 1,2,4,5 tetrazine. These functions are well known to those skilled in the art to be useful in click chemistry reactions. This type of reaction has in particular been described by Sharpless (Angewandte Chemie International Edition 40 (11): 2004-2021). A commonly used chemical chemistry reaction is the Huisgens cycloaddition reaction between an azide and an alkyne. Where the groups may be substituted, they may be substituted by one or more substituents, preferably one, two or three substituents. The substituents may be selected, for example, from the group consisting of halo, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano, haloalkoxy, haloalkyl. DETAILED DESCRIPTION Synthesis Process The present invention relates to a process for the synthesis of triazacyclonane (tacn) and N- and / or C-functionalized tacn derivatives, these compounds corresponding to the general formula (I ") Rb, N / - Wherein R, Rb and Rc may be the same or different and each represents a hydrogen atom, or 0, 1, 2, 3, 4, 5 or 6, preferably n is 0, 1, 2 or 3, and R 'represents a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group, comprising 1 to 12 carbon atoms; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro, amino, halo, alkoxy and hydroxy radicals; an unsubstituted methyl pyridine group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; a quinoline group; an SH group; a group -C (= O) -OR'1 in which R'1 represents a hydrogen atom or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-hydrosuccinimide (NHS), sulfo-NHS group; a group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (= O) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents - a group - (CH2) n -OR'1 in which n and R1 are as defined above, preferably ethoxy, OH; - a - (CH2) .- C group (= 0 In which m represents an integer between 1 and 4 and R 1 is as defined above; an alkyl group comprising 1 to 12 carbon atoms, preferably a methyl; R represents an atom of hydrogen or a group A; A represents a group - (CH2) wA 'wherein w represents an integer between 0 and 4, preferably w is equal to 0 or 1, and A' represents a saturated or unsaturated aliphatic group; , branched or unbranched, substituted or unsubstituted, having 1 to 12 carbon atoms, a cyano group, preferably A 'represents a cyano group when w is 0, an aliphatic or aromatic group containing a function likely to lead to click chemistry reactions, and more particularly a group containing an azo function ture, alkyne, cyclooctene or 1,2,4,5 tetrazine; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; an unsubstituted methyl pyridinic group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; a group (CH 2) w-NA "A" in which w is as defined above, preferably w is equal to 1, and in which A "and A" are identical or different and each represents an atom of hydrogen; a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; a group - (CH2) nA "1 in which n is as defined above and A" 1 represents a saturated or unsaturated, branched or unbranched aliphatic chain, substituted or unsubstituted, which may contain from 1 to 4 units (C = 0) or (C = S), and / or one or more heteroatoms, one or more meso and / or para and / or ortho substituted aromatic groups; preferably A "1 is - (CH2) nC (= O) -A" 1 wherein n is as defined above, preferably n is 0 or 1, and A "'1 is - a -OY group in which Y represents a hydrogen or branched or unbranched alkyl group, preferably Y represents a hydrogen or tert-butyl; a saturated or unsaturated, branched or unbranched aliphatic group containing 1 to 12 carbon atoms; a benzyl group substituted in the para position by a group chosen from cyano, nitro, isothiocyanate, amino and alkoxy groups, preferably the group - (CH 2) n A - 1 is a group -CH 2 -C (= O) - OH, -CH2-C (= O) -OtBu, -CH2-P (= O) - (Me) OCH2CH2COOH, -CH2PhOCH2CCH, -C (= O) CH2CH2COOH, -C (= O) -CH2PhNO2, -C ( = O) -CH2PhNH2 or -C (= O) -CH2PhNCS; a -C (= O) -Z group in which Z represents an organic fluorescent unit, such as, for example, fluorescein, rhodamine, polymethine, boron dipyrromethene, porphyrin, phthalocyanine, squaraine or a derivative of these groups. When A represents a group (CH2), - NA "A" 'in which at least one of A "or A" represents -C (= O) -Z group in which Z represents an organic fluorescent unit, the coupling of The fluorescent unit with the macrocyclic unit is preferentially made by peptide coupling, via an amino acid spacer or not. According to a preferred embodiment, the fluorescent unit is more particularly a boron dipyrromethene type unit (Bodipy®) preferably comprising a COOH or NH 2 type linking functional group. The C-functionalized tacn derivatives as well as the C- and N-functionalized tacn derivatives are more specifically represented by the general formula (I); while tacn and its N-functionalized derivatives are more specifically represented by the general formula (I '): Rb, N' Rc NiA 1 Rb, N / - \ N "Rc Ni 1 Ra Ra (I ') ) (r) and their salts, wherein Ra, Rb, Rc and A are as defined in the general formula (I ").

The formula (I) corresponds to the general formula (I ") in which R is a group A. The formula (I ') corresponds to the general formula (I") in which R is a hydrogen atom. The process for the preparation of the compounds of formula (I ") comprises the steps shown in Scheme 3: NNHHN-ID 1 step (a), step (b) -H 'v3 NI, N" -R3 'R2' N 12 '(IV) CI R1-X r - \ k, step (c) a. Rb, (N + "-R3 or step (d) N / -" Rc LN, X-, N, 2 R Ra i R2 (I ") (V) Scheme 3. Process for the synthesis of the compounds of formula ( I ") In particular, the steps (c) and (d) leading from the compound (V) to the compound (I") are as follows (FIG. 4), the steps represented in dotted lines being optional: R 1, R 3 R2 (V) step (c) step (d) Nucleophilic Nr reduction R1, N1- \ N "R2 (a) step (s) (c ') step (s) (d') Y: V: ## STR2 ## Steps (c) and (d) of the process for the synthesis of the compounds of Formula (I ") Compounds (Ia) and (Ia) are particular cases of the formulas (I) and (I ') respectively, which themselves constitute particular cases of the general formula (I") as mentioned above, steps (c), (c '), (d) and (d') involve chemical modifications known to those skilled in the art, so the essential point is to have a method of preparation effective and versatile d Thus, the present invention relates to a process for the preparation of a compound of the formula (V) R1, N1-N-Ni-N1 R2 (la) R1, n- In which X represents a radical chosen from bromo, iodo or chloro radicals; R1 represents a radical (CH2) n-B wherein n is an integer of 1 to 4; B represents a hydrogen atom; an unsubstituted phenyl radical or a phenyl radical substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro and amino radicals; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy; an unsubstituted pyridine radical or a pyridine radical substituted with one or more radicals chosen from cyano, nitro and amino radicals; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy; R2 represents R1, R2 ', R2' modified by reaction with R1-X or a Boc group, with R2 'representing a hydrogen atom or an aliphatic or aromatic group, optionally substituted with one or more radicals chosen from cyano radicals, nitro, amino, halo, alkoxy, hydroxy, preferably R2 'is H or - (CH2) 2NH2; preferably R2 is R1 or (CH2) 2N (141) 2; R3 represents R1, R3 ', R3' modified by reaction with R1-X or a Boc group, with R3 'representing a hydrogen atom or an aliphatic or aromatic group, optionally substituted with one or more radicals chosen from cyano radicals, nitro, amino, halo, alkoxy, hydroxy, preferably R3 'is H or - (CH2) 2NH2; preferably R3 is R1 or (CH2) 2N (141) 2; preferably, {R2, R3} is {R1, R1}, R1, (CH2) 2N (141) 21, 1 (CH2) 2N (141) 2, R1} or {Boc, Boc}; comprising the following successive reaction steps (a) and (b): a step (a) in which the compound of formula (II) NHHN-D 1 \ 3 R2 '(II) in which R2' and R3 'are such as defined above, preferably {R2 ', R3'} is {H, H}, {H, (CH2) 2NH2}, {(CH2) 2NH2, H}; selectively reacts with the compound of formula (III) (OH) Cl (III) to form the compound of formula (IV) wherein R 2 'and R 3' are as defined above, preferably {R2 ', R3'} is {H, H}, {H, (CH2) 2NH2}, {(CH2) 2NH2, H}; step (a) being optionally followed, when {R2 ', R3'} represents (H, H), an intermediate step (a ') in which the compound (IV) is brought into contact with Boc2O to form the compound (IV ') ## STR1 ## a step (b) during which the compound of formula (IV) or (IV') obtained at step (a) or (a ') reacts with R1-X wherein R1 and X are as defined above, to form the compound of formula (V). According to one embodiment, the invention relates to a process for the preparation of a compound of formula (V ') Rb, ## STR1 ## in which X represents a radical chosen from the bromo, iodo or chloro radicals; Ra, Rb and Re are as defined above, comprising the process for preparing the compound (V) of the invention in which {R2, R3} represents (Boc, Boc) and further comprising a step of deprotection in an acidic medium, optionally followed by one or more steps (e) capable of leading, after chemical modifications known to those skilled in the art, to the compound of formula (V ') According to one embodiment, the invention relates to a process for the preparation of a compound of formula (I ") Rb, N / -N" Rb, R-R (I ") and its salts, wherein Ra, Rb, Rc and R are as defined above comprising the process for preparing the compound of formula (V) or (V ') described above and further comprising step (c) or and ape (d) following - step (c): step in which the compound of formula (V) obtained in step (b) reacts with a NuM reagent, in which Nu represents a carbon nucleophile (carbanion) such as by example CN, alkyl, aryl or malonate and M represents a metal element such as for example Na, K, Li or MgX in which X represents bromo, iodo or chloro, NuM represents for example NaCN, to form the compound of general formula (la R 1, R 1, R 2, N N "-) CN) - R 2 (la) or its salts, wherein R 1, R 2, R 3 and Nu are as defined above; said step (c) being optionally followed by one or more steps (c ') capable of leading (by) chemical modification (s) known to those skilled in the art to the compound of formula (I) Rb ## STR2 ## wherein R a, R b, R c and A are as defined above; step (d): step of which the compound of formula (V) obtained in step (b) is reacted with a reducing agent capable of releasing hydrides H-, such as for example NaBH 4, LiAlH 4, LiAlH (OMe) 3, LiAlH (OtBu) 3, DIBALH to form the compound of the general formula (I 'a) R' 1 N I- \ N N. 3 Ni I R1 '2 (I' a) or its salts, wherein R1 ", R2" and R3 represent respectively R1 , R2 and R3 as defined above or their derivatives formed by reaction with the reducing agent used in step (d), said step (d) being optionally followed by one or more steps (d ') likely (s) to driving after known chemical modification (s) of humans in the art to the compound of formula (I ') Rb, N / - Rc N 1 Ra (I') or its salts, wherein Ra, Rb and Rc are as defined above.

According to a first particular embodiment, the process of the invention comprises the formation, by the steps (a) and (b) described above, of the compound of formula (V-Bn), corresponding to the compound (V) in wherein R1, R2 and R3 are the same and represent unsubstituted benzyl, (V-Bn) or its salts, wherein X is as defined above, and further comprises the step of (d) reducing during wherein the compound (V-Bn) undergoes a nucleophilic attack by a reducing agent, such as, for example, sodium borohydride, to give the compound of formula (I'a-Bn): ## STR2 ## I 'a-Bn) or its salts. According to one embodiment, when the process of the invention leads to the compound of formula (I'a-Bn), the process may further comprise a step (1) of catalytic hydrogenation then leading to the compound (tacn) which corresponds to the formula (I ') in which Ra, Rb and Re are identical and represent a hydrogen atom: (tacn) or its salts. Thus, according to one embodiment of the invention, the synthesis of tacn comprises the steps represented in the following scheme: ## STR2 ## step (a) N NH step (b) / NH NH 2 + ## STR2 ## step (d) NaBH 4 Bn,, X-Bn (V-Bn) Bn, Bn N "step (of 1) NHHN JHJ In one embodiment, the method of the invention leads to the compound (tacn) and further comprises at least one further (2) subsequent step leading to the functionalization of the three nitrogen atoms of the macrocycle by a method known to those skilled in the art (see, for example, JPL Cox et al J. Chem Soc., Perkin Trans, 1990, 2567-2576, AN Singh et al. Bioconjugate Chem., 2011, 22, 1650-1662, PJ Riss et al., Bioorg, Chem Chem Leu, 2008, 18, 5364-5367, J. Simecek et al., Inorg Chem 2012, 51, 577-590, Lukes et al, Chem Eur J, 2010, 16, 714-7185) According to a second particular embodiment, the method of the invention leads, by steps (a), (b) and (c), to the formation of a compound of formula (Ia-i): D (la-i) or its salts, wherein D represents a hydrogen atom or a radical chosen from cyano, nitro and amino radicals; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy, and E represents a CH group or a nitrogen atom.

According to one embodiment, when the process of the invention leads to the compound of formula (Ia-i), the process may further comprise a reduction step (c1), preferably with lithium aluminum tetrahydride, then leading to the compound of formula (Ii): DNN (Ii) or its salts, wherein D and E are as defined above. According to one embodiment, when the process of the invention leads to the compound of formula (Ii), the process may further comprise an additional subsequent step (c'2) in which the NH 2 group of (Ii) is functionalized according to a suitable treatment within the abilities of those skilled in the art, such as, for example, N-alkylation or N-arylation by nucleophilic substitution reactions, nucleophilic addition or reductive amination of aldehydes, to form the compound of formula (I-ii): D- / NN (I-ii) or its salts, wherein D, E, A "and A" are as defined above. According to a particular embodiment, when the process of the invention leads to the compound of formula (Ii) or to the compound (I-ii) in which D is a hydrogen atom and E is a CH group, the process may furthermore comprising a further catalytic hydrogenation subsequent step (c'3) leading to the compound of formula (I-iii): ## STR2 ## or its salts, wherein A "and As is defined above, according to a particular embodiment, when the process of the invention leads to the compound of formula (I-iii), the process may further comprise an additional subsequent step (c'4). ) leading to the functionalization of the three nitrogen atoms of the macrocycle by the introduction of groups Ra, Rb and Rc as defined above, by a method known to those skilled in the art (see for example JPL Cox et al. Chem Soc., Perkin Trans., 1, 1190, 2567-2576, AN Singh et al., Bioconjugate Chem., 2011, 22, 1650-166. 2, P. J. Riss et al., Bioorg. Med. Chem. Lett., 2008, 18, 5364-5367, J. Simecek et al., Inorg. Chem. 2012, 51, 577-590, J. Jeong M. et al., J. Nucl. Med. 2008, 49, 830-836), resulting in the compound of the general formula (I-iv) Rb, / N / - R NN / A (I-iv) or its salts, in which Ra, Rb, Rc, A "and A" are as defined above.

According to a particular embodiment, the process of the invention leads to the compound (I-iv) in which Ra, Rb and Rc are identical and preferably represent: a group - (CH2) nC (= O) -OR ' Wherein R'1 and n are as defined above; Ra o a group - (CH2) n-C (= O) -NR'1 wherein R'1 and n are as defined above; or o a group -P (= O) -R'2R'3 in which R'2 and R'3 are as defined above.

As illustrated in the examples below, the process of the invention allows the direct synthesis of functionalized N- and / or C- triazacyclononanes, which represent macrocycles with a high added value. Targeted systems are obtained in a few steps from commercially available compounds. In contrast to the syntheses described in the prior art, none of the steps of the process of the invention requires special conditions such as carrying out the reaction in high dilution, the use of a prolonged treatment in concentrated acid medium, or a working in an inert atmosphere. The method of the invention can therefore be used on a large scale. The mild conditions of the process of the invention allow the introduction of very diverse organic functions, unlike methods involving tosyle groups. New C-functionalized agents based on triazacyclononane have thus been prepared according to the method of the invention. The present invention relates to novel macrocyclic compounds derived from 1,4,7-triazacyclononane (tacn) having a functional group at a carbon atom of the macrocycle, referred to as "C-functionalized tacn derivatives". According to one embodiment, the C-functionalized tacn derivatives of the present invention are of the general formula (I) Rb, N / - \ N "Rc, NA 1 Ra (I) and its salts, wherein Ra, Rb and Rc may be the same or different and each represents a hydrogen atom, or o - a group - (CH2) nR 'wherein n is 0, 1, 2, 3, 4, 5 or 6, preferably n is 0, 1, 2 or 3 and R 'represents a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having from 1 to 12 carbon atoms, an unsubstituted benzyl group or a substituted benzyl group. meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro, amino, halo, alkoxy, hydroxy, an unsubstituted methyl pyridine group or a methyl pyridine group substituted with one or more groups chosen from cyano, nitro, amino, halo, alkoxy, hydroxy, quinoline group, SH group; -C (= O) -OR'1 group wherein R'1 represents a hydrogen atom or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-hydrosuccinimide (NHS) or sulfo-NHS group; a group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (= O) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents - a group - (CH2) n -OR'1 in which n and R'1 are as defined above, preferably ethoxy, OH; - a group - (CH2) .- Where m represents an integer between 1 and 4 and R'1 is as defined above; an alkyl group having 1 to 12 carbon atoms, preferably methyl; A represents o a group - (CH2) wA 'in which w represents an integer between 0 and 4, preferably n is equal to 0 or 1, and A' represents a saturated or unsaturated, branched or unbranched aliphatic group, substituted or unsubstituted substituted, having 1 to 12 carbon atoms, a cyano group, preferably A 'represents a cyano group when w is 0, an aliphatic or aromatic group containing a function likely to lead to click chemistry reactions, and more particularly a group containing an azide, alkyne, cyclooctene or 1,2,4,5 tetrazine moiety; unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; an unsubstituted methyl pyridinic group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, halo, alkoxy, hydroxy; a group (CH 2) w-NA "A" in which w is as defined above, preferably w is equal to 1, and in which A "and A" are identical or different and each represents an atom of hydrogen; a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; a group - (CH2) nA "1 in which n is as defined above and A" 1 represents a saturated or unsaturated, branched or unbranched aliphatic chain, substituted or unsubstituted, which may contain from 1 to 4 units (C = 0) or (C = S), and / or one or more heteroatoms, one or more meso and / or para and / or ortho substituted aromatic groups; preferably A "1 is - (CH2) nC (= O) -A" 1 wherein n is as defined above, preferably n is 0 or 1, and A "'1 is - a -OY group in which Y represents a hydrogen or branched or unbranched alkyl group, preferably Y represents a hydrogen or tert-butyl; a saturated or unsaturated, branched or unbranched aliphatic group containing 1 to 12 carbon atoms; a benzyl group substituted in the para position by a group chosen from cyano, nitro, isothiocyanate, amino and alkoxy groups, preferably the group - (CH 2) n A - 1 is a group -CH 2 -C (= O) - OH, -CH2-C (= O) -OtBu, -CH2-P (= O) - (Me) OCH2CH2COOH, -CH2PhOCH2CCH, -C (= O) CH2CH2COOH, -C (= O) -CH2PhNO2, -C ( = 0) -CH2PhNH2 or -C (= O) -CH2PhNCS; a -C (= O) -Z group in which Z represents an organic fluorescent unit, such as, for example, fluorescein, rhodamine, polymethine, boron dipyrromethene, porphyrin, phthalocyanine, squaraine or a derivative of these groups. According to one embodiment, the compounds of general formula (I) are as defined above, with the proviso that: when Ra, Rb and Rc are identical and represent hydrogen atoms, then A is not Me, iPr, CH2Bz, CH2NHBz, (CH2) 4NHBz, CH2Ph, CH2PhNH2, CH2Ph (p-NO2), CH2Ph (p-NHCOPh), CH2PhNCS, CH2PhCOPh, or (CH2) 4NHCOPh; when Ra, Rb and Rc are identical and represent methyl, then A is not Me, (CH2) 9CH3, CN, CH2NH2, CH2NHBoc, CH2NHAc, CH2Ph or iPr; when Ra, Rb and Rc are identical and represent CH2COOEt groups, then A is not (CH2) 4NHCOPh or (CH2) 4NHBz; when Ra, Rb and Rc are identical and represent CH2COOtBu groups, then A is not CH2Ph (p-NO2); when Ra, Rb and Rc are identical and represent CH2COOH groups, then A is not CH2Ph (p-NCS), CH2Ph (p-NO2), CH2Ph (p-NH2), CH2Ph (pNHCOCH2Br), CH2Ph (p -NHCOPh), (CH2) 4NH2, (CH2) 4NHBz, Ph (p-NCS), butyl-N-2 - ((6-vinylpyridin-2-yl) methoxy) acetamide, CH2Ph (p-NHC (S) NH In a particular embodiment, A is not a benzyl or an alkyl group having from 1 to 8 carbon atoms. According to a particular embodiment, when Ra, Rb and Rc are identical or different and represent - (CH2) '- R' in which R 'represents an aliphatic group, a substituted or unsubstituted benzyl group, a substituted methylpyridine group or unsubstituted, - (CH 2) 2-OR '1, then A is not benzyl or an alkyl group having from 1 to 8 carbon atoms According to a particular embodiment, when the compounds of general formula (I ) are salts and Ra, Rb and Rc are the same or different and represent an atom of hydrogen or a substituted or unsubstituted alkyl group, then A is not a substituted or unsubstituted alkyl group. According to one embodiment, the compounds of general formula (I) are salts and in this case, the counterion is preferably derived from Cl, Br, I, TFA (trifluoroacetic acid). According to one embodiment, the compounds of general formula (I) can be obtained by the method of the present invention.

The compounds of formula (I) according to the present invention consist of a ring core comprising three nitrogen atoms connected in pairs by an ethylene unit and a functional group A carried by the carbon skeleton. The three nitrogen atoms may or may not be substituted by groups Ra, Rb and Rc. According to a particular embodiment, Ra, Rb and Rc are coordinating groups capable of completing the coordination sphere during the incorporation of a metal ion. The compounds of the present invention have the advantages of the functionalization of nitrogenous macrocycle ligands, namely to offer the possibility of introducing a new functionality on the macrocyclic molecule while retaining the three groups Ra, Rb and Rc to complete the sphere of coordination of the metal that can be complexed. According to one embodiment, the compounds of the invention are of general formula (Ia): ## STR1 ## and its salts, in which R 1 represents a radical (CH 2) wherein n is an integer of 1 to 4, B is a hydrogen atom, an unsubstituted phenyl radical or a phenyl radical substituted in the meso and / or para and / or ortho position by one or more radicals selected from cyano, nitro, amino, halo, preferably bromo or iodo, alkoxy, preferably methoxy, hydroxy, unsubstituted pyridine or pyridine substituted with one or more radicals selected from cyano, nitro, amino; halo, preferably bromo or iodo, alkoxy, preferably methoxy, hydroxy, R2 represents R1, R2 ', R2' modified by reaction with R1-X or a Boc group, with R2 'representing a hydrogen atom or a group aliphatic or aromatic, optionally substituted with an o a plurality of radicals selected from cyano, nitro, amino, halo, alkoxy, hydroxy, preferably R2 'is H or - (CH2) 2 NH2; Preferably R2 is R1 or (CH2) 2N (141) 2; R3 represents R1, R3 ', R3' modified by reaction with R1-X or a Boc group, with R3 'representing a hydrogen atom or an aliphatic or aromatic group, optionally substituted with one or more radicals chosen from cyano radicals, nitro, amino, halo, alkoxy, hydroxy, preferably R3 'is H or - (CH2) 2NH2; preferably R3 is R1 or (CH2) 2N (141) 2; preferably, {R2, R3} is {R1, R1}, {R1, (CH2) 2 N (141) 21, {(C12) 2 N (R1) 2, R1} or {Boc, Boc}; Nu represents a carbon nucleophilic group, Nu represents, for example, CN, an alkyl group, an aryl group and a malonate group. According to one embodiment, the compounds of the invention are of general formula (Ib): NHHN, NE1,2-A (Ib) and its salts, wherein A is as defined in formula ( I). According to one embodiment, the preferred compounds of formula (Ib) are those wherein A represents a group - (CH 2) w-NA "A" wherein w, A "and A" 'are as defined above; preferably A represents - (CH2) -NA "A" and in this case is of specific formula (I-iii).

According to one embodiment, the compounds of the invention are of general formula (Ic): ## STR1 ## (Ic) and its salts, wherein A, n and R 'are as defined in formula (I). According to one embodiment, preferred compounds of formula (Ic) are those in which n is equal to 1 and R 'represents a -C (= O) -OR'i group in which R'1 represents a hydrogen atom. or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl group.

According to one embodiment, preferred compounds of formula (Ic) are those in which n is equal to 1 and R 'represents a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above and R" 1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen atoms, nitrogen or sulfur; preferably, R "1 represents a methyl, ethyl, methoxy or ethoxy group, and preferably R '1 represents P (= O) -Me (OEt) According to one embodiment, preferred compounds of formula (Ic) are those in which which n is 0 and R 'represents an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro, amino and halo radicals, preferably bromo, iodo or fluoro, alkoxy, preferably methoxy, hydroxy, preferably R 'represents an unsubstituted benzyl group According to one embodiment, preferred compounds of formula (Ic) are those in which n is 0 and R represents an unsubstituted methyl pyridine group or a methyl pyridine group substituted with one or more groups selected from cyano, nitro, amino, halo, preferably bromo or iodo, alkoxy, preferably methoxy, hydroxy, preferably R ', is an unsubstituted methyl pyridinic group.

According to one embodiment, preferred compounds of formula (Ic) are those in which n is 0, R 'represents an unsubstituted benzyl or methyl pyridine group, substituted by one or more groups selected from cyano, nitro groups. amino; halo, preferably bromo or iodo; alkoxy, preferably methoxy, and A represents - (CH2) NH2 represented by the specific formula (I-i).

According to one embodiment, preferred compounds of formula (Ic) are those in which n is 0, R 'represents an unsubstituted benzyl or methyl pyridine group, substituted by one or more groups selected from cyano, nitro groups. amino; halo, preferably bromo or iodo; alkoxy, preferably methoxy; and A represents a group - (CH2) NA "A" wherein A "and A" 'are as defined above, represented by the specific formula (I-ii). According to one embodiment, preferred compounds of formula (Ic) are those in which n is 0, R 'represents an unsubstituted benzyl or methyl pyridine group, substituted by one or more groups selected from cyano, nitro groups. amino; halo, preferably bromo or iodo; alkoxy, preferably methoxy; and A represents a cyano group, represented by the specific formula (la-i). According to one embodiment, the compounds of the invention are of general formula (Id): ## STR2 ## and its salts, in which Ra, Rb, Rc, w and A 'are as defined in formula (I). (CH 2) 1, - A' According to one embodiment, preferred compounds of formula (Id) are those in which w is 0 and A 'is a According to one embodiment, preferred compounds of formula (Id) are those in which w is 0, A 'represents a cyano group and Ra, Rb and Rc are identical and represent a group - (CH2) nR wherein n is preferably 0 and R 'is unsubstituted benzyl or benzyl substituted in the meso and / or para and / or ortho position by one or more radicals selected from cyano, nitro, amino; halo, preferably bromo, iodo or fluoro, alkoxy, preferably methoxy, hydroxy, more preferably R 'is unsubstituted benzyl According to one embodiment, the compounds of the invention are of general formula (Ic): ## STR2 ## (le) and its salts, wherein Ra, Rb, Rc, w, A "and A" are as defined in formula (I). According to one embodiment, preferred compounds of formula (Id) are those wherein w is 1, represented by the specific formula (I-iv). According to one embodiment, preferred compounds of formula (Id) are those in which w is equal to 1 and A "represents a hydrogen atom and A" 'represents a -C (= O) -Z group in which Z represents an organic fluorescent unit, such as, for example, fluorescein, rhodamine, polymethine, boron dipyrromethene, porphyrin, phthalocyanine, squaraine or a derivative of these groups; preferably Z represents a dipyrromethene group of boron.

According to a particular embodiment, the compounds (I) of the invention are such that Ra, Rb and Rc are identical and represent groups of the CH2COOH, CH2COOtBu or CH2COOEt type and A is a -CH2NH2 function. By chemical reactions within the reach of those skilled in the art, such as, for example, N-alkylation or N-arylation by nucleophilic substitution reactions, nucleophilic addition, or a reductive amination of aldehydes, the -CH 2 NH 2 function optionally activated, it is possible to couple the macrocycle to a solid support or a biological support. In particular, the -CH 2 NH 2 function, modified or not with groups capable of reacting with functions such as, for example, NH 2, SH, COOH, azide or alkyne, can react with NH 2, SH, COOH, azide or alkyne functions, or other reactive functions present on the solid or biological support to be functionalized. By "biological support" is meant biological molecules such as whole antibodies, antibody fragments, peptides, oligonucleotides, aptamers or recombinant proteins. According to a particular embodiment, the biological molecule is not the folate or a folate derivative. By "solid support" is meant silica gel or organic polymer. Nanoparticle labeling is also possible. In a particular embodiment, the compounds of formula (I) of the invention are the following: - 1,4,7-tribenzyl-1,4,7-triazacyclononane-2-carbonitrile (4) - (1,4 , 7-Tribenzyl-1,4,7-triazacyclonon-2-yl) methanamine (5) - (1,4,7-triazacyclonon-2-yl) methanamine (6) - tert-butyl tribenzyl-1,4,7-triazacyclononan-2-yl) methylcarbamate (7) tert-butyl ((1,4,7-triazacyclononan-2-yl) methyl) carbamate (8) -tert-butyl ((1.4.7 -tris ((ethoxy (methyl) phosphoryl) methyl) -1,4,7-triazacyclononan-2-yl) methyl) carbamate (9) - (2- (aminomethyl) -1,4,7-triazacyclononan-1,4 , 7-triyl) tris (methylene)) tris (methylphosphinic acid) (10) tri-tert-butyl-2,2 ', 2 "- (2 - ((bis (2- (tert-butoxy) -2-oxoethyl) ) amino) methyl) -1,4,7-triazacyclononane-1,4,7-triethyl) triacetate (11) acid 2,2 ', 2 "- (2 - ((bis (carboxymethyl) amino) methyl) -1 4,7-triazacyclononane-1,4,7-triyl) triacetic acid (12) N - ((1,4,7-triazacyclononan-2-yl) methyl) -1- (4- (prop-2-yn) 1-yloxy) phenyl) methanamine (14) tri-tert-butyl-2,2 ', 2 " - (2 - (((4- (prop-2-yn-1-yloxy) benzyl) amino) methyl) -1,4,7-triazacyclononane-1,4,7-triyl) triacetate (15) (1, 4,7-triazacyclononan-2-yl) -BODIPY (16) and their salts. In another aspect, the invention also relates to macrocyclic metal complexes derived from the compounds of formula (I). According to one embodiment, the metal complex according to the invention comprises a ligand of formula (I) according to the invention and a metal, preferably in the form of a bi-tri or tetravalent ion, chosen from the group comprising Zn, Ca, Be, Mg, Sr, Cu, Ba, Cd, Cr, Mn, Fe, Co, Ni, Al, Ga, In, Zr, Tc, Gd, Y, Lu, At, Pb, Sc, Tb, Eu, Yb, other lanthanides or one of their radioactive isotopes. According to one embodiment, the complexed metal is preferably an ion derived from metals Al, In, Ga, Zr and Cu. According to one embodiment, the complexed metal in the macrocyclic cavity is preferably a bi-tri or tetravalent ion such as for example Zn 2+ ions Ca 2+, Be 2+, Mg 2+, Sr 2+, Cu 2+, Ba 2+, Cd 2+, Cr 2+, Mn 2+, Fe2 +, Co2 +, Ni2 +, / V +, Ga3 +, In3 +, Cr3 +, Mn3 +, Fe3 +, Zr4 +. When the macrocyclic metal complex derived from the compounds of formula (I) is used for PET imaging, the complexed metal is preferably 68Ga, 64Cu, Sc 20 or 89Zr. The metal can also be Al to enable 18F labeling for PET imaging. When the macrocyclic metal complex derived from the compounds of formula (I) is used for TEMP imaging, the complexed metal is preferably 111In, 99mTc or 67Ga. When the macrocyclic metal complex derived from the compounds of formula (I) is used for radiotherapy, preferably radioimmunotherapy, the complexed metal is preferably 90Y, 177Lu, 211At, 212Pb, Sc or 64 / 67Cu. When the macrocyclic metal complex derived from the compounds of formula (I) is used for MRI imaging, the complexed metal is preferably Gd or Mn.

When the macrocyclic metal complex deriving from the compounds of formula (I) is used for fluorescence imaging or PARACEST MRI, the complexed metal is preferably a lanthanide, preferably Tb, Eu or Yb. The present invention also relates to the compounds of formula (V ') Rb, r-1, NF "-Rc N, X-1 Ra (V') ) X represents a radical chosen from the bromo, iodo or chloro radicals; Ra, Rb and Rc may be identical or different and each represents a hydrogen atom, or o a - (CH2) nR 'group in which n is equal to at 0, 1, 2, 3, 4, 5 or 6, preferably n is 0, 1, 2 or 3 and R 'represents a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group, comprising 1 to 12 carbon atoms; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more radicals selected from cyano, nitro, amino, halo, alkoxy, hydroxy,; an unsubstituted methyl pyridine group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, amino, halo, alkoxy, hy droxy; quinoline group; SH group; a group -C (= O) -OR'1 in which R'1 represents a hydrogen atom or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-hydrosuccinimide (NHS), sulfo-NHS group; a group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (= O) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents - a - (CH 2) n -OR '1 group in which n and R' 1 are as defined above, preferably ethoxy, OH; - a - (CH 2). In which m represents an integer between 1 and 4 and R'1 is as defined above; an alkyl group having 1 to 12 carbon atoms, preferably methyl. the compounds of formula (V ') are as defined above, with the proviso that Ra, Rb and Rc are not simultaneously three methyl groups.

In a preferred embodiment, Ra and Rc represent groups of (C = O) OtBu and Rb type a group of alkyl or benzyl type. This embodiment notably makes it possible to access selectively N-functionalised systems by successive reactions within the reach of those skilled in the art. Use of the compounds of the invention As mentioned above, the compounds (I "), in particular of formula (I), of the present invention can serve as ligands to form a metal complex. (I "), in particular of formula (I) 'of the invention can be used as chelating agents for the purification of liquids, in particular to remove traces of metal elements. In particular, the compounds of formula (I ") of the invention can be used for the decontamination of radioactive effluents and for the elimination of toxic heavy metals According to one embodiment, the compounds of formula (I"), in particular of formula (I), of the invention can be used for the development of new MOF-type coordination polymers ("Metal-Organic Framework") selectively trapping certain gases. These three-dimensional systems can be prepared by self-assembly of polycarboxylic molecular bricks of formula (I "). According to one embodiment, the metal complexes derived from the compounds of formula (I"), in particular of formula (I), can be used as catalysts.

In particular, they can be used as catalysts in epoxidation reactions, especially asymmetric epoxidation reactions. According to one embodiment, the metal complexes derived from the compounds of formula (I "), in particular of formula (I), can be used as imaging agents and / or radiotherapy. also the use of the complexes according to the invention for imaging by single photon emission computed tomography (TEMP), positron emission tomography (PET) or magnetic resonance imaging (MRI). According to one embodiment, the metal complexes derived from the compounds of formula (I "), in particular of formula (I), may be used as biomolecule markers, in particular as peptide or antibody markers. The present invention also relates to compounds obtained by the coupling of a biological molecule with a ligand of formula (I) according to the invention, complexed or not with a metal. When coupling the ligand of the invention with a biological molecule, a spacer group may be used between the ligand and the biological molecule. According to one embodiment, the spacer may for example be a PEG group.

EXAMPLES The present invention will be better understood on reading the following examples which illustrate the invention in a nonlimiting manner. Example A: Preparation of the 1,4,7-triazacyclononane compound (tacn) (3) 1 Preparation of the reaction intermediate octahydroimidazol [1,2-a [pyrazine] -N, N, N, C, (1) A solution of chloroacetaldehyde (50% in H 2 O, 98.8 g, 0.63 mol) in 500 mL of acetonitrile is added dropwise at 20 ° C to a solution of diethylenetriamine (64.9 g, 0.5 g). 63 mol) and K 2 CO 3 (1.23 mol, 173.9 g, 2 eq) in 1 L of acetonitrile The mixture is stirred at room temperature for 6 h After filtration through celite, the solvent is evaporated 800 mL of diethyl ether are added to the residual oil, the insoluble impurities are removed by filtration and after evaporation of the solvent, the compound 1 is obtained in the form of a yellow oil (m = 56.8 g, yield = 71% 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.60-1.81 (bs, 2H, NH), 1.93 - 2.04 (m, 2H), 2.23 (b.p. dd, 1H, 2J = 11.6 Hz, 3J = 8.0 Hz, CH 2 CH), 2.43-2.45 (m, 2H), 2.56-2.63 (m, 3H), 2.73; -2.77 (m, 2 H), 2.87 (dd, 1H, 2J = 11.6, 3J = 2.6 Hz, CH 2 CH). 13 C {1 H} NMR (75 MHz, CDCl 3, 298 K) (ppm): 42.1; 44.3; 48.4; 50.2 51.6 (CH2a); 75.7 (CH). Preparation of the reaction intermediate 1,4,7-tributyl-1,4,7-triazacyclononane NH (2) 353.9 g of benzyl bromide (2.06 mol, 3 equivalents) are added dropwise at 10 ° C. ° C to a solution of 1 (87.61 g, 0.69 mol) and 380 g of potassium carbonate (2.76 mol, 4 equivalents) in 1.8 L of acetonitrile. The mixture is stirred at ambient temperature for 24 hours. After filtration on celite, the solvent is evaporated, and 1.8 L of ethanol are added to the residual oil. 26 g of sodium borohydride (0.69 mol, 1 equivalent) are added at -10 ° C. After 12 hours, the solvent is evaporated and the oil is taken up in chloroform and ether. The solvent is evaporated and the oil is taken up in ethanol (200 mL) and 100 mL of hydrochloric acid are added. The mixture is evaporated to dryness and 500 ml of acetone are added to the residual oil, the white precipitate formed is isolated by filtration and then recrystallized from water (400 ml). The crystals are filtered, a solution of 13 M NaOH is slowly added until a pH> 12 is obtained. After extraction with chloroform, the organic phase is dried over MgSO 4. After filtration and evaporation of the solvent, the compound 2 is obtained in the form of a colorless oil (m = 102 g, yield = 37%). 1 H NMR (300 MHz, CDCl 3, 300 K) δ (ppm): 2.86 (s, 12H); 3.65 (s, 6H); 7.28-7.36 (m, 15H). 13C NMR (1H) (75 MHz, CDCl3, 300 K) δ (ppm): (CH2) 55.4 (δ6); (CH2) 63.0 (* 3); (CH (br)) 126.7 (* 3); 128.1 (* 6); 129.1 (* 6); (Car) 140.4 (* 3). MALDI-TOF: m / z = 399.87 [M +]. Preparation of the compound 1,4,7-triazacyclononane (tacn) (3) 84.77 g of the compound 2 (0.21 mol) are placed in 1 L of acetic acid with 9 g of 10% Pd / C ( 8 mmol, 0.04 equivalents) under H2. After consumption of 14.3 L of hydrogen (0.63 mol, 3 equivalents), the mixture is filtered on celite and the solvent is evaporated. 52 ml of hydrochloric acid are added, followed by 250 ml of ethanol. The precipitate obtained is filtered and washed with 200 mL of diethyl ether. Compound 3 is obtained in the form of a white solid (25 g, yield = 95%). 1 H NMR (300 MHz, D 20, 300 K) δ (PPrn): 3.47 (s, 12H). 13 C NMR (1H) (75 MHz, D 20, 300 K) at (ppm): (CH 2) 42.4. MALDI-TOF: m / z = 129.70 [M.I.

Example B: Preparation of the compound (1,4,7-triazacyclononan-2-yl) methanamine (6) 4 Preparation of the reaction intermediate 1,4,7-tributyl-1,4,7-triazacyclononane-2-carbonitrile ( 4) 259.3 g of benzyl bromide (1.5 mol, 3 equivalents) are added dropwise to a solution of 1 (64.3 g, 0.5 mol) and 278.8 g of K 2 CO 3 (2, 0 mol, 4 equivalents) in 1.1 L of acetonitrile at 10 ° C. The mixture is stirred for 12 hours. 24.76 g of sodium cyanide (0.505 mol, 1 eq) are added cautiously. The mixture is stirred at room temperature for 4 days. After filtration on celite, the solvent is evaporated, 3 L of diethyl ether are added to the residual oil and the insoluble impurities are removed by filtration. After evaporation of the solvent, the compound 4 is obtained in the form of a brown oil (137.2 g, yield = 63%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.53-1.78 (m, 1H); 2.43-2.56 (m, 4H); 2.66-2.74 (m, 1H); 2.82-2.88 (m, 2H); 2.95-2.99 (m, 1H); 3.14-3.22 (m, 1H); 3.42-3.53 (m, 1H); 3.63-3.84 (m, 6H); 7.19-7.33 (m, 15H). 13 C NMR (1H) (75 MHz, CDCl 3, 298 K) δ (ppm): 54.7 (CH); 55.5; 56.4; 57.4; 58.8; 61.4; 62.1; 63.5; 65.9 (CH2a); 118.0 (CN); 126.8; 127.1; 127.7; 128.0; 128.1; 128.2; 128.3; 128.4; 128.6; 128.8; 129.0; 129.1 (* 2); 129.2; 129.4 (CHar) 138.2; 139.3; 139.9 (Car). ESI-MS: m / z = 398.24 [M-CN + 2Hr; 425.25 IM + Hr. IR (cm-1): 2250 (CN). Preparation of the reaction intermediate (1,4,7-tribenzyl-1,4,7-triazacyclonon-2-yl) methanamine (5) A solution of 4 (112.7 g, 0.27 mol) in 450 mL THF is added very slowly at -78 ° C under nitrogen to a suspension of 11.5 g of LiAlH4 (0.32 mol, 1.2 eq) in 450 mL of THF. The mixture is stirred for 12 hours. 100 mL of water is carefully added to the mixture. After evaporation of the solvent, the gray-green solid obtained is taken up in 1 L of chloroform, the solution is filtered on celite to remove impurities. After evaporation of the solvent, the residual brown oil is placed in 200 ml of acetone and 200 ml of 37% HCl are slowly added. The white precipitate is isolated by filtration and recrystallized from water to give the protonated form of compound 2 (83.9 g, 0.20 mol). The compound is deprotonated by addition of a 16 M sodium hydroxide solution until a pH of 12 is obtained. After extraction with chloroform (2 × 500 ml) and drying of the organic phase over MgSO 4, the solvent is evaporated. Compound 5 is obtained as a yellow oil (45.3 g, yield = 39%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.45 (m, 2H); 2.39-2.86 (m, 10H); 3.03-3.11 (m, 1H); 3.35-3.75 (m, 7H); 3.85 (bs, 1H); 7.24-7.44 (15H). 13 C {1 H} NMR (75 MHz, CDCl 3, 298 K) δ (ppm): 42.5; 51.1; 52.8; 55.1; 55.6; 57.9; 58.2 (CH2a); 62.8 (CH); 63.5; 64.3 (CH2a) 126.7; 127.0; 127.1; 128.3 (* 9); 128.8; 129.2; 129.5 (CHar); 140.2; 140.4; 141.2 (Car). ESI-MS: m / z = 429.31 [M + H] +. HMRS-ESI: m / z = calcd for C28H36N4 + H: 429.3012, obtained 429.3060. Preparation of (1,4,7-triazacyclononan-2-yl) methanamine / -NH-IHN-1-NH2 (6) Compound 5 (5.0 g, 11.7 mol) ) is dissolved in a mixture of acetic acid (29 mL), water (29 mL) and THF (98 mL). 500 mg of 10% Pd / C (0.47 mmol, 0.04 equivalents) are added under H2. After consumption of the expected hydrogen volume, the palladium is removed by filtration on celite. After evaporation of the solvent, the residue is dissolved in ethanol (100 mL). 5 ml of 37% hydrochloric acid are then added. After 1 hour, the precipitate formed is isolated by filtration and then washed with 20 ml of ethanol. The precipitate is recrystallized from water. The compound is deprotonated by addition to the crystals of a 16 M sodium hydroxide solution until a pH of 12 is obtained. After extraction with chloroform (2 × 500 ml), and drying of the organic phase over MgSO 4, the solvent is evaporated. allowing to obtain 6 in the form of a yellow oil (m = 0.79 g, yield = 44%). 1 H NMR (300 MHz, D 20, 300 K) δ (ppm): 2.98 - 3.58 (m, 13H). 13 C NMR (1H) (75 MHz, D 20, 300 K) δ (ppm): (CH 2) 40.9; 42.0; 42.9; 45.2; 46.2; 47.2; (CH) 50.6. MALDI-TOF: m / z = 158.74 [41]. Example C: Preparation of the tert-butyl (tacn) methylcarbamate compound (8) Preparation of the reaction intermediate tert-butyl (1,4,7-tributyl-1,4,7-triazacyclononan-2-yl) methylcarbamate (7) A solution of Boc 2 O (4.20 g, 19.2 mmol) in CH 2 Cl 2 (100 mL) was slowly added to 5 (8.24 g, m.p. 19.2 mmol) in CH2Cl2 (150 mL). The solution is stirred at ambient temperature for 24 hours. After evaporation of the solvent, the oil is purified by chromatography on alumina (eluent: CH 2 Cl 2) making it possible to obtain compound 7 in the form of a yellow oil (m = 7.38 g, yield = 73%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.42 (s, 9H, CH 3); 2.34-2.67 (m, 8H); 2.83-2.92 (m, 1H); 2.97-3.16 (m, 2H); 3.35-3.65 (m, 7H); 4.05 (m, 1H); 4.94 (m, 1H); 7.15-7.33 (m, 15H). 13 C NMR (1H) (150 MHz, CDCl 3, 298 K) δ (ppm): 28.7 (3 3) (CH 3); 40.7; 50.6; 53.2; 55.3; 56.2; 57.9; 58.1 (CH2); 58.5 (CH); 63.8; 64.2 (CH2); 79.0 (C); 126.8; 127.0; 127.2; 128.4 (* 6); 129.0 (* 2); 129.2 (* 2); 129.5 (* 2) (CHar); 140.1; 140.3; 140.7 (Car); 156.3 (C = O). ESI-MS: m / z = 529.35 [M + H] +. HMRS-ESI: m / z = calcd for C33H44N4O2 + H: 529.3537 obtained 529.3528. Preparation of the compound tert-butyl ((1,4,7-triazacyclononan-2-yl) methyl) carbamate NHHN 0 1-1 N ---- 7-7-1N-- 0 .... _ k_ (8) Compound 7 (3.33 g, 6.30 mmol) is dissolved in a mixture of acetic acid (20 mL), water (20 mL) and THF (60 mL). 266 mg of 10% Pd / C (0.25 mmol, 0.04 equivalents) are added under H2. After consumption of the expected hydrogen volume, the palladium is removed by filtration on celite. After evaporation of the solvent, the residue is dissolved in ethanol (100 mL). 5 ml of a 3M hydrochloric acid solution are then added. After 1 hour, the precipitate formed is isolated by filtration and then washed with 20 ml of ethanol and dried in vacuo to give a white powder. The compound is deprotonated by addition of a 3M sodium hydroxide solution. After extraction with chloroform (2 × 50 ml), and drying of the organic phase over MgSO 4, the solvent is evaporated to obtain 8 in the form of an oil. yellow (m = 1.30 g, yield = 80%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.39 (s, 9H, CH 3); 2.35-3.24 (m, 13H); 4.28-4.55 (m, 3H, NH); 5.83 (s, 1H, NHC = 0), 13 C (1 H) NMR (150 MHz, CDCl 3, 298 K) δ (ppm): 28.6 (3 3) (CH 3); 43.1; 44.0; 44.6; 45.6; 45.9 (CH2); 46.8 (CH); 79.5 (C); 156.8 (C = O). ESI-MS: m / z = 203.15 [M-Su + H] +; 259.15 [M + H] +. HMRS-ESI: m / z = calcd for C12H27N4O2: 259.212; obtained 259.2116. Example D: Preparation of the compound (2- (aminomethyl) -1,4,7-triazacyclononane-1,4,7-triyl) tris (methylene)) tris (methylphosphinic acid) (10) Preparation of the reaction intermediate tert -butyl ((1,4,7-tris ((ethoxy (methyl) phosphoryl) methyl) -1,4,7-triazacyclononan-2-yl) methyl) carbamate 0, EtO / - 1: Me PN N 0 8 N ---) 1 \ -INI <o_k_ L, 0 P% Me 'OEt (9) 420 mg of 8 (1.12 mmol) and 818 mg of diethoxymethylphosphine (6.01 mmol) are placed in a balloon bubbled with nitrogen for 5 min. The mixture is then heated to 80 ° C. 189 mg of paraformaldehyde (6.01 mmol) are added and the mixture is stirred for 2 h. After returning to ambient temperature, water is added (5 ml) and a solution of 3M HCl is added in order to reach a pH of 5. The solution is washed twice with 30 ml of diethyl ether. A 3M NaOH sodium hydroxide solution is slowly added until a pH of 13 is reached. The aqueous phase is washed with 2 * 50 mL of chloroform. The organic phase is dried over MgSO4. After evaporation of the solvent, the residual oil is purified by flash chromatography on silica (A: CH 2 Cl 2, B: MeOH, B 0% -> 60%, rt = 4.2 min). Compound 9 is obtained in the form of a yellow oil (m = 360 mg, yield = 58%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.30 (t, 9H, 2 J = 7 Hz, PCH 3); 1.41 (s, 9H, CH3); 1.45-1.54 (m, 9H, PCH 2 CH 3); 2.77-3.15 (m, 19H); 4.06 (m, 6H, PCH 2 CH 3); 5.83 (s, 1H, NH). Preparation of the compound (2- (aminomethyl) -1,4,7-triazacyclononane-1,4,7-triyl) tris (methylene)) tris (methylphosphinic acid) 0 'pH HI / - P-1) 10 ml of a 37% solution of HCl are added over 60 mg of the compound 9 (0.10 mmol). After evaporation, the compound (3 HCl) was isolated as a white powder (m = 54.4 mg, yield = 100%) .1H NMR (500 MHz, D 2 O 298 K) δ (ppm): 1.37-1.49 (m, 9H), 2.82-3.60 (m, 19H).

NMR 31 P {1H} NMR (202 MHz, D 20, 298 K) δ (ppm): 38.4; 45.2; 49.2. ESI-MS: m / z = 435.17 [M + H] +; 457.15 [M + Na] +. HMRS-ESI: m / z = calcd for C13H33N4O6P3 + H: 435.1686; obtained 435.1666; calcd for C13H33N4O6P3 + Na: 457.1505; obtained 457.1511. Example E: Preparation of 2,2 ', 2 "- (2 - ((bis (carboxymethyl) amino) methyl) -1,4,7-triazacyclononane-1,4,7-triyl) triacetic acid (12) Preparation of the reaction intermediate tri-tert-butyl-2,2 ', 2 "- (2 - ((bis (2- (tert-butoxy) -2-oxoethyl) amino) methyl) -1,4, 7-triazacyclononane-1,4,7-triyl) triacetate 0. 7.01 (N / A) N-O-N-O-O-O-0 (11) A bromoacetate solution tertbutyl (4.66 g, 23.89 mmol) is added to a solution of 6 (756 mg, 4.79 mmol) and K2CO3 (6.61 g, 4.89 mmol) in 16 mL of acetonitrile. The mixture is heated at 45 ° C. for 24 hrs After returning to ambient temperature, the solution is filtered on celite and the solvent is evaporated off The residual oil is taken up in ether and the impurities are removed by filtration. purified by alumina chromatography (eluent: 99: 1 CH2Cl2 / MeOH) to give 11 as a yellow oil (m = 1.89 mg, Yield = 54%) .1H NMR (300 MHz, CDCl3, 298) K) - (ppm): 1 38-1.41 (m, 45H, CH3); 2.43 (dd, 1H, J = 13.2, 7.7 Hz); 2.60-3.11 (m, 11H); 3.19-3.45 (m, 10H); 4.02-4.13 (m, 1H). 13C NMR (1H) (75 MHz, CDCl3, 298K)? (Ppm): 28.4 (? 15) (CH3); 52.4; 53.6; 54.7; 55.3; 55.4; 55.7; 55.9; 56.0; 56.2; 57.0; 59.8; 61.1 (CH 2 + CH); 80.4; 80.6; 80.7; 80.8 (* 2) (C); 171.0 (* 2); 171.7; 171.8; 172.3 (C = O). ESI-MS: m / z = 729.5 [M + H] +; 751.5 [M + Na] +. Preparation of 2,2 ', 2 "- (2 - ((bis (carboxymethyl) amino) methyl) -1,4,7-triazacyclononane-1,4,7-triyl) triacetic acid HO HO - (12) mL of a 37% solution of hydrochloric acid is added over 50 mg of compound 11 (0.07 mmol). for 1 hour at room temperature After evaporation of the solvent, the precipitate obtained is washed with 40 ml of acetone After filtration, the compound 12 is obtained in the form of a white solid (m = 360 mg, yield = 58% ESI-MS: m / z = 449.3 [M + H] +, 471.2 [M + Na] +, 493.2 [M + 2NaH] + HMRS-ESI: m / z = calculated for C17H28N4O10 + H: 449.1888, obtained 449.1858 Example F: Preparation of the compound 1,4,7-tris (pyridin-2-ylmethyl) -1,4,7-triazacyclononane (13) N / NN / - (9.85 g) 2- (bromomethyl) pyridine bromohydrate (39.0 mmol, 3 eq) are added slowly at 10 ° C to a solution of 1 (1.62 g, 13.0 mmol) and 45.5 g of K2CO3 in 90 OH mL of acetonitrile. at room temperature for 24 hours. After filtration on celite, the solvent is evaporated. The residual oil is taken up in 200 mL of diethyl ether and the solution is stirred for 24h. The precipitate is isolated by filtration, washed with 20 ml of diethyl ether and then dried in vacuo to give 12.96 g of the reaction intermediate. 5.0 g of this intermediate (10.3 mmol) are placed in 45 ml of ethanol and 3.9 g of NaBH4 (103.0 mmol) are added at -10 ° C. After 12 h, the solvent is evaporated and 50 mL of diethyl ether are added to the residual oil. The impurities are removed by filtration and the solvent is evaporated. Compound 13 is obtained in the form of an orange oil (m = 1.62 g, yield = 31%).

1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 3.06 (s, 12H); 4.34 (s, 6H); 7.80-7.84 (m, 3H); 7.92-7.95 (m, 3H); 8.33-8.39 (m, 3H); 8.64-8.66 (m, 3H). 13 C {1 H} NMR (75 MHz, CDCl 3, 298 K) δ (ppm): 49.3 (* 6); 56.3 (* 3); 126.4 (* 3); 127.3 (* 3); 143.5 (* 3); 145.6 (* 3); 150.3 (* 3). ESI-MS: m / z = 403.26 [M + H] +. Example G: Preparation of the compound N - ((1,4,7-triazacyclononan-2-yl) methyl) -1- (4- (prop-2-yn-1-yloxy) phenyl) methanamine (15) Preparation of the reaction intermediate N4 (1,4,7-triazacyclononan-2-yl) methyl) -1- (4- (prop-2-yn-1-yloxy) phenyl) methanamine; ----) 1 -IN (14) 101 mg of 3- (prop-2-ynyloxy) benzaldehyde (0.63 mmol) are added to a solution of 6 (100 mg, 0.63 mmol) in 25 mL ethanol, and the mixture is stirred at room temperature for 48h. The solvent is then evaporated and 25 ml of diethyl ether are added to the residual oil. After 12h, the impurities are removed by filtration on celite. The solvent is evaporated, the oil is placed in 10 mL of ethanol and 250 mg of NaBH4 (6.7 mmol) is added at 0 ° C. The mixture is stirred at ambient temperature for 24 hours. The solvent is evaporated, 25 mL of dichloromethane is added to the residual solid and the impurities are removed by filtration. The solution is washed with a 3M sodium hydroxide solution (10 mL), dried over MgSO 4 and the solvent is evaporated. Compound 14 is obtained as a white solid (m = 135 mg, yield = 68%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.10-1.60 (m, 3H); 2.30-2.90 (m, 15H); 3.65 (s, 2H); 4.61 (d, 2H, 4 J = 2.3 Hz); 6.86 (d, 2H, 3 J = 8.7 Hz); 7.18 (d, 2H, 3 J = 8.7 Hz). 13C NMR (1H) (75 MHz, CDCl3, 298K)? (Ppm): 46.0; 46.4; 47.0; 47.2; 47.3; 49.9; 53.6; 55.6; 55.9; 75.6; 78.8; 114.8 (* 2); 129.3 (* 2); 130.1; 156.6. ESI-MS: m / z = 303.22 [M + H] +.

Preparation of the tri-tert-butyl-2,2 ', 2 "- (2 - (((4- (prop-2-yn-1-yloxy) benzyl) amino) methyl) -1,4,7-compound triazacyclononane-1,4,7-triyl) triacetate A solution of tertbutyl bromoacetate (341 mg, 1.75 mmol) was added to a solution of 14 (135 mg, 0.44 mmol) and K2CO3 (484 mg, 3%). 50 mmol) in acetonitrile (15 ml) The mixture is heated at 45 ° C. for 24 hours After returning to ambient temperature, the solution is filtered on celite The solvent is evaporated, 50 ml of diethyl ether are added The impurities are removed by filtration and the solvent is again evaporated The oil is purified by chromatography on alumina (eluent: CH 2 Cl 2 / MeOH 99: 1). yellow oil (m = 100 mg, yield = 30%) .1H NMR (300 MHz, CDCl3, 298 K) δ (ppm): 1.36-1.42 (m, 36H); 1H, 2 J = 2.49 Hz), 2.50-3.77 (m, 23H), 4.61 (d, 0 1 (15) 2H, 4 J = 2.3 Hz), 6.83 (d, 2H, 3J = 8.2 Hz); 7.18 (d, 2H, 3J = 8.2 Hz) ESI-MS: m / z = 759.50 [M + H] +; 771.57 [M + Na] +. Example H: Preparation of the compound (1,4,7-triazacyclonon-2-yl) -dipyromethene of boron also called (1,4,7-triazacyclononan-2-yl) -BODIPY (16) / -NHHN INI, 195 mg of 4,4-difluoro-8- (4 - ((1-carboxy-2- (4-nitrophenyl) ethyl) carbamoyl) phenyl) 1,3,5,7-tetramethyl-2,6-diethy-4 -bora-3α, 4α-diaza-s-indacene (0.32 mmol), 42 mg of hydroxybenzotriazole (HOBt) (0.32 mmol) and 60 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (0.32 mmol) are added successively to a solution of 6 (50 mg, 0.32 mmol) in 10 mL of DMF. The mixture is stirred at room temperature and the reaction is monitored by TLC (CH 2 Cl 2 / MeOH / NH 4 OH 10: 85: 5). The solvent is then evaporated. The red oil is dissolved in 20 mL of dichloromethane and washed three times with 10 mL of water. The organic phase is isolated and then dried over MgSO4. The red oil is purified by chromatography on silica gel (80: 20 EtOH / NH4OH). The oil obtained is then taken up in a CH 2 Cl 2 / hexane mixture, the precipitate formed is isolated by filtration. Compound 16 is obtained in the form of a red solid (m = 180 mg, yield = 74%). 1 H NMR (300 MHz, MeO D, 300 K) δ (ppm): 0.94 (t, 6H, 3 J = 7.5 Hz), 1.24 (s, 6H); 2.29 (q, 4H, 3 J = 7.5 Hz); 2.38 (s, 6H); 2.48-2.60 (m, 1H); 2.61-3.22 (m, 12H); 3.27- 3.40 (m, 2H); 4.83-4.90 (m, 1H); 7.39 (d, 2H, 3 J = 8.1 Hz); 7.54 (d, 2H, 3J = 8.5 Hz); 7.93 (d, 2H, 3 J = 8.5 Hz); 8.11 (d, 2H, 3 J = 8.1 Hz). HN H 0 N O (16) Example I: Preparation of di-tert-butyl hexahydroimidazo [1,2-alpyrazine] -7-dicarboxylate compound (17) ## STR1 ## A solution of Boc 2 O (5.79 g, 26.6 mol) diluted in 30 mL of dichloromethane is added dropwise to a solution of 1 (1.69 g, 13.3 mmol) in dichloromethane (30 mL). The mixture is stirred at ambient temperature for 24 hours. After evaporation of the solvent, the oil is taken up in 50 ml of diethyl ether and the impurities are removed by filtration. Compound 17 is isolated as a light brown solid (m = 3.98 g, yield = 91%). 1 H NMR (300 MHz, CDCl 3, 298 K)? (Ppm): 3.32-3.39 (m, 18H); 4.37-4.67 (m, 2H); 4.73-5.98 (m, 8H); 6.44 (m, 1H). ESI-MS: m / z = 328.15 [M + H] +. Example J: Preparation of the compound 4-benzyl-1,7-bis (tert-butoxycarbonyl) octahydro-1H-imidazo [1,2-a] pyrazin-4-ium bromide (18) A solution of benzyl bromide (742 mg, 4 , 3 mmol) diluted in acetonitrile (5 mL) is added at 0 ° C to a solution of 17 (1.45 g, 4.34 mmol) in acetonitrile (10 mL). The mixture is stirred at ambient temperature for 24 hours. After evaporation of the solvent, the oil is taken up in 20 ml of diethyl ether, the precipitate is filtered, washed with 2 * 10 ml of diethyl ether and dried under vacuum. Compound 18 is obtained under N-Boc (LN, Br Boc (18) as a beige solid (m = 1.31 g, yield = 61%) .1H NMR (500 MHz, CDCl3, 320 K) δ (ppm) : 11.35 (s, 9H), 1.51 (s, 9H), 3.58-3.66 (m, 2H), 3.70-3.78 (m, 1H), 3.81-3. 93 (m, 3H); 4.13-4.20 (m, 1H); 4.46 (m, 1H); 4.56-4.65 (m, 1H); 4.75 (d, 1H); Y = 12.3 Hz), 4.83 (m, 1H), 5.19 (m, 1H), 5.46 (d, 1H, 2 J = 12.3 Hz), 7.45-7.51; (m, 3H) 7.59 (d, 2H, 3 J = 7.1 Hz) ESI-MS: m / z = 418.27 [M-Br] + Example K: Preparation of 4-benzyloctahydro- 1H-Imidazo [1,2-alpyrazin-4-bromide (19) 0.7 mL of 1M HCl solution are added very slowly over 18 (0.34 mg, 0.7 mmol). After 1 hour of evaporation of the solvent, the compound 19 is obtained in the form of a white solid (m = 0.07 mg, yield = 36%) 1 H NMR (300 MHz, CDCl 3, 298 K). (ppm): 3.09-3.11 (m, 2H), 3.34-3.48 (m, 8H), 4.37 (s, 2H), 5.30-5.34 (m, 1H); 7.52 (m, 5H) ESI-MS: m / z = 218.16 [M-Br] + .exe Example L Preparation of the compound 1,7-bis (tert-butoxycarbonyl) -4-methyloctahydro-1H-imidazo [1,2-alpyrazin-4-iodide (20) N, N + Boc A solution of iodomethane (0.92 mg, 6.5 mmol) in acetonitrile (5 mL) is added dropwise at 0 ° C to a solution of 17 (2.12 g, 6.5 mmol) in acetonitrile (10 mL). The mixture is stirred for 24 hours at room temperature. After evaporation of the solvent, the oil is taken up in 30 ml of diethyl ether, the precipitated product is filtered and then washed with 2 ° C. 10 ml of diethyl ether and dried under vacuum. Compound 20 is obtained as a yellow solid (m = 1.78 g, yield = 59%). 1 H NMR (300 MHz, CDCl 3, 298 K) δ (ppm): 1.40-1.48 (m, 21H); 3.70-4.74 (m, 10H); 5.0 (m, 1H). ESI-MS: m / z = 230.12 [M-I-2tBu + 2H] +, 286.19 [M-I-tBu + H] +; 342.25 [M-I [±. Example M: Preparation of the compound (1,4,7-triazonan-2-yl) methanamine (23) Preparation of the reaction intermediate 2- (hexahydroimidazo [1,2-a] pyrazin-7 (1H) -yl) ethanamine (21) A solution of chloroacetaldehyde (50% in water, 2.36 g, 15 mmol) is added to a solution of triethylenetetraamine (3 g, m.p. 15 mmol) in 70 mL of acetonitrile at room temperature. The mixture is stirred for 5 hours. After evaporation of the solvent, the two isomers 21 and 21 'are obtained in the form of a yellow oil and will be used without additional purification (m = 2.55 g, yield = 100%). 13 C NMR (1H) (75 MHz, CDCl 3, 300 K)? (Ppm): (CH 2) 38.8; 40.8; 41.7; 43.6; 45.0; 48.7; 49.3; 49.4; 49.9; 51.0; 52.0; 52.1; 52.4; 52.6; (CH) 75.8; 81.7. MALDI-TOF: m / z = 170.71 [4141.

Preparation of N, N-dibenzyl-2- (4,7-dibenzyl-1,4,7-triazacyclononan-1-yl) ethanamine Reaction Intermediate (22) 45.55 g of benzyl bromide (0.27 g) mol, 4 equivalents) are slowly added to a solution of 21 and 21 '(11.32 g, 66 mmol) and 37.3 g of potassium carbonate (0.27 mol, 4 equivalents) in 250 mL of acetonitrile. The mixture is stirred at room temperature for 24 hours. After filtration on celite, the solvent is evaporated, the oil is taken up in 250 ml of ethanol and 2.5 g of sodium borohydride (66 mmol, 1 equivalent) are added at 0 ° C. After 12 h, the solvent is evaporated and 150 mL of chloroform is added. The insoluble impurities are removed by filtration. After evaporation of the solvent, the oil is purified by chromatography on alumina (solvent: CH 2 Cl 2). After evaporation of the solvent, 500 ml of pentane are added to the residual oil, the solution is filtered and the solvent is evaporated. Compound 22 is obtained in the form of a yellow oil (m = 16 g, 30 mmol, yield = 45%). 1 H NMR (300 MHz, CDCl 3, 300 K) δ (ppm): 2.49 - 2.87 (m, 16H); 3.47 (s, 2H); 3.56 (s, 4H); 3.64 (s, 2H); 7.22-7.41 (m, 20H). 13 C {1 H} NMR (75 MHz, CDCl 3, 300 K) δ (ppm): (CH 2) 51.4; 52.2; 52.3; 52.3; 55.4; 55.8; 56.3; 58.8 (* 2); 58.9; 59.3; 63.2; (Cflar) 126.8 (* 4); 128.1 (* 8); 128.7 (* 8); (Car) 139.8 (* 4). MALDI-TOF: m / z = 533.06 [M +].

Preparation of the compound (1,4,7-triazacyclononan-2-yl) methanamine NH 2 (23), 4 HCl 12.37 g of 22 (23 mmol) are placed in 130 ml of acetic acid with 1 g of Pd / C at 10% (0.04 equivalents, 1 mmol) under H2. After consumption of 2.06L of hydrogen (0.92 mol, 4 equivalents), the palladium is removed by filtration and the solvent is evaporated. 7.7 ml of 37% HCl are added to the residual oil and then 50 ml of ethanol, forming a white precipitate. After filtration, the compound 23 is obtained in the form of a white solid (m = 7.3 g, 23 mmol, yield = 100%). 1 H NMR (300 MHz, D 2 O, 300 K) at (ppm): 3.33 - 3.57 (m, 16H). 13 C NMR (1H) (75 MHz, D 20, 300 K) δ (PPn 1): (CH 2) 35.3 (* 2); 43.3 (* 2); 43.3; 44.6 (* 2); 51.7. MALDI-TOF: m / z = 172.41 [M.I.

Claims (6)

REVENDICATIONS1. Compound of general formula (V ') Rb, - Rc X-Ra (V') X represents a radical chosen from bromo, iodo or chloro radicals; Ra, Rb and Rc may be the same or different and each represents: o a hydrogen atom, or o a - (CH2) .- R 'group in which n is 0, 1, 2, 3, 4, 5 or 6, preferably n is 0, 1, 2 or 3 and R 'is: - a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro, amino, halo, alkoxy and hydroxy radicals; an unsubstituted methyl pyridine group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; a quinoline group; an SH group; a group -C (.0) -OR'1 wherein R'1 represents a hydrogen atom or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-hydrosuccinimide (NHS), sulfo-NHSun group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (= O) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents: - a group - (CH2) n -OR'1 in which n and R'1 are as defined above, preferably ethoxy, OH; - a - (CH2) .- C group (= 0) -OR'i in which m represents an integer between 1 and 4 and R'1 is as defined above; - an alkyl group comprising 1 to 12 carbon atoms, preferably methyl; provided that Ra, Rb and Rc are not simultaneously three methyl groups. 2. Compound of general formula (I) Rb, wherein: Ra, Rb and Rc may be the same or different and each represents: o a hydrogen atom, or o a group - (CH 2) n -R 'wherein n is 0, 1, 2, 3, 4, 5 or 6, preferably n is 0, 1, 2 or 3 and R' is: a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; - an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or a plurality of radicals chosen from cyano, nitro, amino, halo, alkoxy, hydroxy radicals; an unsubstituted methyl pyridine group or a methyl pyridine group substituted by one or more groups chosen from cyano, nitro, amino, halo, alkoxy groups, hydroxy; a quinoline group; an SH group; a -C (.0) -OR'1 group in which R'1 represents a hydrogen atom or an ali group; Sodium or unsaturated, branched or unbranched, substituted or unsubstituted phage having 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-norosuccinimide group (NHS) or sulfo-NHS; a group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (.0) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2) nR "1 in which n is as defined above; and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents: - a group - (CH2) .OR'1 in which n and R'1 are as defined above, preferably ethoxy, OH; - a group - (CH2). C (.0) -OR'i wherein m represents an integer between 1 and 4 and R'1 is as defined above; an alkyl group having 1 to 12 carbon atoms, preferably methyl; A represents: - a group - (CH 2) n - A 'in which w represents an integer between 0 and 4, preferably n is equal to 0 or 1, and A' represents: - a saturated or unsaturated aliphatic group, branched or unbranched, substituted or unsubstituted, having 1 to 12 carbon atoms; - a cyano group, preferably A 'represents a cyano group when w is 0; an aliphatic or aromatic group containing a function likely to lead to click chemistry reactions, and more particularly a group containing an azide, alkyne, cyclooctene or 1,2,4,5 razine; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; an unsubstituted methyl pyridinic group or a methyl pyridinic group substituted by one or more groups chosen from cyano, nitro, halo, alkoxy and hydroxy groups; a group (CH 2) w-NA "A" in which w is as defined above, preferably w is equal to 1, and wherein A "and A" 'are identical or different and each represents: an atom hydrogen; a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; a group - (CH2) '- A "1 in which n is as defined above and A" 1 represents a saturated or unsaturated, branched or unbranched aliphatic chain, substituted or unsubstituted, which may contain from 1 to 4 units (C = O) or (C = S), and / or one or more heteroatoms, one or more meso and / or para and / or ortho substituted aromatic groups; preferably A - 1 is - (CH2) .- C (= O) - A - 1 in which n is as defined above, preferably n is 0 or 1, and A '' 1 represents a group -OY in which Y represents a hydrogen or a branched or unbranched alkyl group, preferably Y represents a hydrogen or a tert-butyl; a saturated or unsaturated aliphatic group, branched or unbranched, comprising 1 to 12 carbon atoms; a benzyl group substituted in the para position by a group selected from cyano, nitro, isothiocyanate, amino, alkoxy, preferably - (CH2) .- A-1 is a -CH2-C group (= O) -OH, -CH2-C (= O) -OtBu, -CH2-P (= O) - (Me) OCH2CH2COOH, -CH2PhOCH2CzCH, -C (= O) CH2CH2COOH, -C (= O) - CH2PhNO2, C (= O) -CH2PhNH2 or -C (= O) -CH2PhNCS; a group -C (= O) -Z in which Z represents an organic fluorescent unit, such as, for example, fluorescein, rhodamine, polymethine, boron dipyrromethene, porphyrin, phthalocyanine, squaraine or a derivative of these groups; with the proviso that: when Ra, Rb and Rc are the same and represent hydrogen atoms, then A is not Me, iPr, CH2Bz, CH2NHBz, (CH2) 4NHBz, CH2Ph, CH2PhNH2, CH2Ph (p-NO2 ), CH2Ph (p-NHCOPh), CH2PhNCS, CH2PhCOPh, or (CH2) 4NHCOPh; when Ra, Rb and Rc are identical and represent methyl, then A is not Me, (CH2) 9CH3, CN, CH2NH2, CH2NHBoc, CH2NHAc, CH2Ph or iPr; when Ra, Rb and Rc are identical and represent CH2COOEt groups, then A is not (CH2) 4NHCOPh or (CH2) 4NHBz; when Ra, Rb and Rc are identical and represent CH2COOtBu groups, then A is not CH2Ph (p-NO2); when Ra, Rb and Rc are identical and represent CH2COOH groups, then A is not CH2Ph (p-NCS), CH2Ph (p-NO2), CH2Ph (pNH2), CH2Ph (p-NHCOCH2Br), CH2Ph (p-NHCOPh), (CF12) 4NE12, (CH2) 4NHBz, Ph (p-NCS), butyl-N-2 - ((6-vinylpyridin-2-yl) methoxy) acetamide, CH2Ph (p-NHC (S) NH-D-Ala-D-Lys (HSG) -D-Tyr-D-Lys (HS G) NH2. 3. Compound of general formula (I) according to claim 2, selected from: 1,4,7-tribenzyl-1,4,7-triazacyclononane-2-carbonitrile; (1,4,7-Tributyl-1,4,7-triazacyclononan-2-yl) methanamine; (1,4,7-triazacyclononan-2-yl) methanamine; tert-butyl (1,4,7-tribenzyl-1,4,7-triazacyclononan-2-yl) methylcarbamate; tert-butyl ((1,4,7-triazacyclononan-2-yl) methyl) carbamate; tert-butyl ((1,4,7-tris ((ethoxy (methyl) phosphoryl) methyl) -1,4,7-triazacyclononan-2-yl) methyl) carbamate; (2- (aminomethyl) -1,4,7-triazacyclononane-1,4,7-triyptris (methylene)) tris (methylphosphinic acid); tri-tert-buty1-2,21,2 "- (2 - ((bis (2- (tert-butoxy) -2-oxoethypamino) methyl) -1,4,7-triazacyclononane-1,4,7-triyl 2,2 ', 2 "- (2 - ((bis (carboxymethylamino) methyl) -1,4,7-triazacyclononane-1,4,7-triyptriacetic acid; N - ((1,4,7- triazacyclononan-2-yl) methyl) -1- (4- (prop-2-yn-1-yloxy) phenyl) methanamine; tri-tert-butyl-2,2,2,2 "- (2 - (((4- (prop-2-yn-1-yloxy) benzyl) amino) methyl) -1,4,7-triazacyclononane-1,4,7-triyptriacetate (1,4,7-triazacyclononan-2-yl) -BODIPY; and their salts. 4. A process for the preparation of a compound of formula (V) wherein X represents a radical chosen from bromo, iodo or chloro radicals; R1 represents a radical (CH2) n-B wherein n is an integer of 1 to 4; B represents a hydrogen atom; an unsubstituted phenyl radical or a phenyl radical substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro and amino radicals; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy; an unsubstituted pyridine radical or a pyridine radical substituted with one or more radicals chosen from cyano, nitro and amino radicals; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy; R2 represents R1, R2 ', R2' modified by reaction with R1-X or a Boc group, with R2 'representing a hydrogen atom or an aliphatic or aromatic group, optionally substituted with one or more radicals chosen from cyano radicals, nitro, amino, halo, alkoxy, hydroxy, preferably R2 'is H or - (CH2) 2N112; preferably R2 represents R1 or (CH2) 2N (R1) 2, R3 represents R1, R3 ', R3' modified by reaction with R1-X or a Boc group, with R3 'representing a hydrogen atom or an aliphatic group or aromatic, optionally substituted with one or more radicals selected from cyano, nitro, amino, halo, alkoxy, hydroxy, preferably R3 'is H or - (CH2) 2NH2; preferably R3 is R1 or (CH2) 2N (R1) 2; preferably, {R2, R3} represents {R1, R1}, R1, (CH2) 2N (R1) 21, {(CH2) 2N (R1) 2, R1} or {Boc, Boc}; comprising the following successive reaction steps (a) and (b): a step (a) in which the compound of formula (II) NHHN n3N, R2I (II) in which R2 'and R3' are as defined above, preferably {R2 ', R3'} is {H, H}, {H, (CH2) 2NH2}, {(cH2) 2NH2, H}; selectively reacts with the compound of formula (III) ## STR2 ## to form the compound of formula (IV) ## STR1 ## wherein R 2 'and R 3' are as defined above, preferably {R2 ', R3'} is {H, H}, {H, (CH2) 2NH2}, {(CH2) 2NH2, H}; step (a) being optionally followed, when {R2 ', R3'} represents (H, H), an intermediate step (a ') in which the compound (IV) is brought into contact with Boc2O to form the compound (IV ') N "-Boc Boc (IV') - a step (b) during which the compound of formula (IV) or (IV ') obtained in step (a) or (a') reacts with R1-X wherein R1 and X are as defined above, to form the compound of formula (V). 5. Process for the preparation of a compound of formula (V ') Rb, n', N +, N-Rc, X-Ra (V ') in which: X represents a radical chosen from bromo, iodo or chloro; Ra, Rb and Re may be the same or different and each represents: o a hydrogen atom; a group - (C112) nR 'in which n is equal to 0, 1, 2, 3, 4, 5 or 6, preferably n is equal to 0, 1, 2 or 3 and R' represents: - a group saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic having 1 to 12 carbon atoms; an unsubstituted benzyl group or a benzyl group substituted in the meso and / or para and / or ortho position by one or more radicals chosen from cyano, nitro, amino, halo, alkoxy and hydroxy radicals; an unsubstituted methyl pyridine group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; a quinoline group; an SH group; a group -C (.0) -OR'1 in which R'1 represents a hydrogen atom or a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group containing 1 to 12 carbon atoms, preferably R'1 represents a hydrogen atom or a methyl, ethyl, tert-butyl, benzyl, pentafluorobenzyl, N-hydrosuccinimide (NHS), sulfo-NHS group; a group - (CH2) 2 -OR'1 in which R'1 is as defined above; a group -C (.0) -NHR'1 in which R'1 is as defined above; a group -P (= O) -R'2R'3 in which R'2 and R'3 may be identical or different and each represent a group - (CH2), - R "1 in which n is as defined herein above and R "1 represents a saturated or unsaturated aliphatic chain, optionally interrupted by one or more oxygen, nitrogen or sulfur atoms; preferably, R "1 represents: - a group - (CH 2) n - OR '1 in which n and R' 1 are as defined above, preferably ethoxy, OH; - a group - (CH 2), - Wherein m represents an integer of from 1 to 4 and R'1 is as defined above; alkyl of 1 to 12 carbon atoms, preferably methyl; comprising the process for the preparation of the compound (V) according to claim 4, wherein {R2, R3} represents {Boc, Boc}; and further comprising a step of deprotection in acidic medium, optionally followed by one or more steps (e). ) which can lead, after chemical modifications, to the compound of formula (V ') A process for the preparation of a compound of formula (I ") Rb, / - Rc / NN" R Ra (I ") and its salts, in which: Ra, Rb and Rc are as defined in claim 5; R represents a hydrogen atom or a group A, with A representing: a group - (CH2) n - A 'in which w represents an integer between 0 and 4, preferably n is equal to 0 or 1 and A 'represents: a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; a cyano group; preferably A 'represents a cyano group when w is 0; an aliphatic or aromatic group containing a function capable of leading to click chemistry reactions, and more particularly a group containing an azide, alkyne, cyclooctene or 1,2,4,5 tetrazine function, an unsubstituted benzyl group or a group benzyl substituted in the meso and / or para and / or ortho position by one or more groups selected from cyano, nitro, amino, halo, alkoxy, hydroxy; an unsubstituted methyl pyridinic group or a methyl pyridinic group substituted with one or more groups selected from cyano, nitro, halo, alkoxy, hydroxy; o a group (CH 2) n - NA "A" wherein w is as defined above, preferably w is 1, and wherein A "and A" are the same or different and each represents: an atom hydrogen; a saturated or unsaturated, branched or unbranched, substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms; a group - (CH2) nA "1 in which n is as defined above and A" 1 represents a saturated or unsaturated, branched or unbranched aliphatic chain, substituted or unsubstituted, which may contain from 1 to 4 units (C = 0) or (C = S), and / or one or more heteroatoms, one or more meso and / or para and / or ortho substituted aromatic groups; preferably A "1 represents a group - (CH 2) n C (= O) - A" 1 in which n is as defined above, preferably n is 0 or 1, and A "1 represents: - a -OY group in which Y represents a hydrogen or branched or unbranched alkyl group, preferably Y represents a hydrogen or tert-butyl; a saturated or unsaturated, branched or unbranched aliphatic group containing 1 to 12 carbon atoms; a benzyl group substituted in the para position by a group chosen from cyano, nitro, isothiocyanate, amino and alkoxy groups, preferably the group - (CH 2) n- is a group -CH 2 -C (= O ) -OH, -CH2-C (= O) -OtBu, -CH2-P (= O) - (Me) OCH2CH2COOH, CH2PhOCH2C = -CH, -C (= O) CH2CH2COOH, -C (= O) -CH2PhNO2 - C (.0) -CH2PliNH2 or -C (= O) -CH2PhNCS a -C (= O) -Z group in which Z represents an organic fluorescent unit, such as for example fluorescein, rhodamine, polymethine, boron dipyrromethene , porphyrin, phthalocyanine, squaraine or a derivative of these groupings; comprising the process for preparing the compound of formula (V) according to claim 4; and further comprising the following step (c) or step (d): step (c): step in which the compound of formula (V) reacts with a NuM reagent, wherein Nu represents a nucleophile carbon such as for example CN, alkyl, aryl or malonate and M represents a metal element such as for example Na, K, Li or MgX in which X represents bromo, iodo or chloro, NuM represents for example NaCN, to form the compound of wherein R1, R2 and R3 are as defined in claim 4 and N1 is as defined above; ; said step (c) being optionally followed by one or more steps (c ') which are capable of leading, by chemical modification (s), to the compound of formula (I) Rc Ra (I) or its salts in which Ra, Rb and Rc are as defined in claim 5 and A is as defined above; step (d): step during which the compound of formula (V) is reacted with a reducing agent capable of liberating 1-1- hydrides, such as for example NaBH 4, LiAlH 4, LiAlH (OMe) 3, LiAlH (OtBu) 3, DIBALH, to form the compound of general formula (I 'a) R 1 "N f" - R 1 "N N" R 2 "(I' a) or its salts, wherein R 1", R 2 "and R 3" represent respectively R1, R2 and R3 as defined in claim 4 or derivatives thereof formed by reaction with the reductant used in step (d); said step (d) being optionally followed by one or more steps (d ') likely to lead after chemical modification (s) to the compound of formula (I') Rb, nRc NN "Ra (I ') or its salts, wherein Ra, Rb and Rc are as defined in claim 5. 7. The process according to claim 6, wherein the process according to claim 4 leads to the compound of formula (V-Bn) (V-Bn ) or its salts, wherein X is as defined in claim 4 and wherein the compound (V-Bn) undergoes a step (d) nucleophilic attack by a reducing agent, such as for example sodium borohydride, to give the compound of formula (I'a-Bn) or its salts, and further comprising a further catalytic hydrogenation step (1) leading to the compound (tacn) NHHN NEfi (tacn) or its salts, and optionally comprising an additional subsequent step (2) of functionalization of the three nitrogen atoms of the macrocycle. claim 6 resulting in the compound of formula (Ia-i) (I 'a-Bn) D-CE NNj-CN or its salts, wherein D represents a hydrogen atom or a radical selected from cyano, nitro radicals amino; halo, preferably bromo or iodo; alkoxy, preferably methoxy; hydroxy, and E represents a CH group or a nitrogen atom; and optionally comprising a subsequent reduction step (c1), preferably with aluminum lithium tetrahydride, resulting in the compound of formula (I-1) D E N N or its salts, wherein D and E are as defined above; and optionally comprising a subsequent step (c'2) in which the NH2 group of (Ii) is functionalized, to form the compound of formula (I-ii) NN z E "or its salts, wherein D and E are as defined above and A "and A" are as defined in claim 6. 9. The process according to claim 8, resulting in compounds of formula (Ii) or (I-ii) wherein D is an atom of hydrogen and E a CH group, further comprising a further catalytic hydrogenation step (c'3) leading to the compound of formula (I-iii) NHHN A "'or its salts, wherein A" and A "are as defined in claim 6; and optionally comprising an additional subsequent step (c'4) leading to the functionalization of the three nitrogen atoms of the (I-iii) macrocycle by the introduction of Ra, Rb and Re groups as defined in claim 5, leading to to the compound of general formula (I-iv) Rb, / Rc / NN "NA" 'Ra A "/ (I-iv) or its salts, wherein Ra, Rb, Rc, A" and A "' are such that defined in claims 5 and 6. A metal complex comprising a ligand of formula (I) according to claim 2 and a metal, preferably in the form of bi-tri or tetravalent ion, selected from the group comprising Zn, Ca, Be, Mg, Sr , Cu, Ba, Cd, Cr, Mn, Fe, Co, Ni, Al, Ga, In, Zr, Tc, Gd, Y, Lu, At, Pb, Sc, Tb, Eu, Yb, other lanthanides or one of their radioactive isotopes. 11. The use of a complex according to claim 10 for single photon emission computed tomography (TEMP), positron emission tomography (PET) or magnetic resonance imaging (min 12). Complex according to Claim 10 as a catalyst for chemical reactions, preferably an epoxidation reaction 13. Use of a compound of formula (I) according to Claim 2 for the purification of liquids, in particular for the removal of traces of metal elements, or for the preparation of coordination polymers selectively trapping a gas.